Published online before print February 13, 2009, doi: 10.1161/CIRCEP.108.790212
Original Articles |
Effects of Chronic Gap Junction Conduction–Enhancing Antiarrhythmic Peptide GAP-134 Administration on Experimental Atrial Fibrillation in Dogs
From the Keenan Research Center, Li Ka Shing Knowledge Institute (G.L., X.H., P.P.-S.S., A.R., P.D.), and Division of Cardiology (H.L.-P., I.M., G.W.M., X.H., P.P.-S.S., A.R., P.D.) St Michael’s Hospital, Toronto, Ontario, Canada; the Department of Medicine (H.L.-P., I.M., G.W.M., E.T., P.D.), University of Toronto, Ontario, Canada; and Wyeth Research (E.I.R., J.K.H.), Collegeville, Pa.
Correspondence to Paul Dorian, MD, St Michael’s Hospital, Division of Cardiology, 30 Bond St, 6-050Q, Toronto, Ontario M5B 1W8, Canada. E-mail dorianp{at}smh.toronto.on.ca
Received May 7, 2008; accepted December 15, 2008.
Background— Abnormal intercellular communication caused by connexin dysfunction may contribute to atrial fibrillation (AF). The present study assessed the effect of the gap junction conduction–enhancing antiarrhythmic peptide GAP-134 on AF inducibility and maintenance in a dog model of atrial cardiomyopathy.
Methods and Results— Twenty-four dogs subject to simultaneous atrioventricular pacing (220 bpm for 14 days) were randomly assigned to placebo treatment (PACED-CTRL; 12 dogs) or oral GAP-134 (2.9 mg/kg BID; PACED-GAP-134; 12 dogs) starting on day 0. UNPACED-CTRL (4 dogs) and UNPACED-GAP-134 (4 dogs) served as additional control groups. Change in left atrial (LA) systolic area from baseline to 14 days was calculated using transoesophageal echocardiography. At 14 days, animals underwent an open-chest electrophysiological study. PACED-CTRL dogs (versus UNPACED-CTRL) had a shorter estimated LA wavelength (8.0±1.4 versus 24.4±2.5 cm, P<0.05) and a greater AF vulnerability (mean AF duration, 1588±329 versus 25±34 seconds, P<0.05). Oral GAP-134 had no effect on AF vulnerability in UNPACED dogs. Compared with PACED-CTRL dogs, PACED-GAP-134 dogs had a longer estimated LA wavelength (10.2±2.8 versus 8.0±1.4 cm, respectively, P<0.05). Oral GAP-134 did not significantly reduce AF inducibility or maintenance in the entire group of 24 PACED dogs; in a subgroup of dogs (n=11) with less than 100% increase in LA systolic area, oral GAP-134 reduced AF induction from 100% to 40% and mean AF duration from 1737±120 to 615±280 seconds (P<0.05).
Conclusions— Oral GAP-134 reduces pacing-induced decrease in LA wavelength and appears to attenuate AF vulnerability in dogs with less atrial mechanical remodeling. Gap junction modulation may affect AF in some circumstances.
Key Words: atrial fibrillation • gap junctions • cardiomyopathy
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